The United States is in the midst of an opioid epidemic. Approved treatments for opioid use disorder (OUD) show only moderate efficacy, and most patients relapse early in treatment. There has been increased interest in the role of the immune system in OUD in terms of both pathophysiology and treatment. Opioids are known to activate microglia ? the brains' innate immune cells ? which leads to an immediate immune response; however, with chronic opioid use, the peripheral immune system becomes suppressed. Persistent, chronic immune activation becomes pathological, and can lead to long-standing, widespread alterations in reward and neurocognitive processes, which negatively impact treatment outcome. Further, while studies have consistently shown that chronic opioid abuse leads to suppressed peripheral immune function, it is not known whether chronic opioid abuse impacts the neuroimmune system. We have developed and validated the tools to measure a marker of microglia in living humans, specifically positron emission tomography (PET) imaging with the radiotracer [11C]PBR28. The overall goal of the proposed project is to use these tools to measure microglia levels in living individuals with OUD compared to healthy controls (Aim 1), and to determine relationships between microglia levels and objective measures of reward processing and neurocognitive function (Aim 2). Findings from this high-risk exploratory R21 proposal will improve our understanding of the neuroimmune mechanisms underlying OUD and its associated clinical correlates. These results have the potential to uncover a novel and treatable neuroimmune mechanism of OUD, and may guide the use of immunomodulatory agents in the clinical treatment of OUD.